ROLE OF LOCOREGIONAL TREATMENT IN THE MANAGEMENT OF

METASTATIC BREAST CANCER

Dr.Sivagnanam Balaji, MD RT, Cancer Institute (WIA),Adyar

AIM OF THE STUDY:

Aim of this retrospective study is to evaluate the role of loco regional

treatment such as local radiotherapy and surgery in the management of patient with

metastatic breast cancer.

MATERIALS AND METHODS:

One hundred and Ninety five patients with metastatic breast cancer between

the years 2003 to 2008 were taken for this retrospective study. Among these,

seventy five patients did not receive locoregional treatment, and the remaining one

hundred and twenty patients received locoregional treatment to the primary.

Locoregional treatment included radiotherapy and surgery.

RESULTS:

Patients survival was analyzed at the end of 1 year, 3 years, 5 years, and at

the end of 10 years. It was found that, in patients receiving concurrent

chemoradiation, survival at the end of 1, 3, 5 and 10 years were 89%, 58%, 46%

and 42% respectively. Similarly, in patients receiving concurrent chemoradiation

followed by surgery, survival was 97%, 80%, 71% and 70% respectively. Further,

survival for chemotherapy was 60%, 5%, 2% and 0% respectively. Again, for the

arm including only radiotherapy, survival was around 67%, 33%, 33% and 33%

respectively. Those patients who receive only hormonal therapy had 50%, 13%,

13% and 13% overall survival at the end of 1, 3,5 and 10 years.

CONCLUSION:

The data reported in this retrospective study confirmed that chemo-radiation

improved overall survival and symptomatic local control, demonstrated in loco-

regionally treated patients with metastatic breast cancer.

1

INTRODUCTION

Evolution of breast cancer

As carcinoma of breast has no clear cause hence gained much

attention throughout the ages all over the world. The story of breast

cancer is complex as there is no happy ending unlike other diseases. The

development and milestones of breast cancer started from the ancient

civilization of the Chinese, Egyptian, Babylonian, Greek, Greeco-

Roman, middle ages Christian, Jewish, Arabic.

The Chinese form of medicine describes five forms of therapy for

tumors.

1. Spiritual care

2. Pharmacology

3. Diet

4. Acupuncture

5. Treatment of specific diseases

2

Egyptian form of medicine was described by IMHOTEP who used

cautery for cancer. Edwin Smith during his period obtained information

from Papyrous roll described that breast cancer that are cold on touch

has no treatment.

During Greek period, Hippocrates described diseases in three

groups.

Curable when medicine

1. Curable by knife

2. Curable by fire

Hippocrates also described that breast cancer was the cessation of

menstruation.

Greeco-Roman period – Aurelius Celsus described breast cancer

as a fixed irregular swelling with dilated veins and ulcers and divided

into four staged

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1. Early cancer

2. Cancer without ulcer

3. Cancer with ulceration

4. Cancer with cauliflower like growth, and advised no treatment

for last three stages.

The first physician who operated breast cancer in the first century

was LEONIDES. His method of surgery was by using incision from the

uninvolved part of the breast and applied cautery to stop bleeding, the

same method was repeated until the whole breast is removed and the

underlying tissue was covered with eschar. Galen described breast

cancer was due to black bile and said breast cancer looks like a crabs leg

and suggested patient to be purged and bleed and to let out the tumor in

early stages.

From Middle Ages – downfall of Romans – beginning of

Renaissance - Christian

During this period the patron of breast disease was Saint Agatha in

the third century whose breast was cut off using sheets

4

Arabic Rhazes advised excision of breast cancer only if it was

completely operable. Hay ben Abbas advised compete excision of the

disease and allowed bleeding to evacuate the bad disease.

Renaissance – from medieval to modern Era

Andreas Vesalius recommended mastectomy for breast cancer and

used sutures instead of cautery. Ambrose Pare described lymph node

metastases of breast cancer. Serventus described the method of removal

of pectoralis muscle with axillary glands. Wilhelm Fabry, father of

German surgery compressed and fixed the base of breast and used knife

to amputate the breast. Johan Schultles, German surgeon, inventor of

surgical instruments .18th Century

Henri Le Dran of France described carcinoma of breast as a

localized disease in early stages and lymph nodal spread as bas disease

with bad prognosis. Jean Petit, friend of Le dran advised surgery of

breast cancer involves removal of breast, pectoral muscles and axillary

nodes. German surgeons, Lorez and Heister advised Guillotine machine

for breast tumor.

5

Heister described the relationship between surgeon and patient and

said that surgeons should be stead fast and not to be disconnected by the

cries of the patient.

19th Century- period of invention of aneasthesia and antisepsis

hence breast cancer surgery improved.

European surgery –

Nooth an English surgeon sprayed carbolic acid over the breast

instead of cautery. Syme described the need for axillary lymph node

dissection in breast cancer patients. Charles Moore believed in extensive

surgery for breast cancer and said that tumor should not be cut as it may

disperse the tumor and allow recurrence of the disease. He also advised

the entire removal of breast with skin and not to remove pectoralis

muscle. Richard Van Volkman advised extensive surgery even for small

tumors. Theodor Billorth also advised the same. Ernst Kuster advised

removal of axillary fat with axillary nodes. Lothar Heidenhain advised

removal of superficial pectoralis major muscle. Everard Home showed

appearance of cancer cells under microscope. Henrich Van

WaldeyerHantz described carcinoma arising from epithelial tissue and

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sarcoma from mesodermal tissue. Victor Cornil described malignant

transformation of acinar epithelium of breast. David Van Hansemann

described diffentiation of cancer cells (ANAPLASIA)

American Surgery

Joseph Pancoast described the pre-anesthetic era of mastectomy

with axillary lymphatic drainage. Samuel.D.Gross described breast

conservation surgery. William Halsted advised removal of breast cancer

with pectoralis muscle. William Meyer modification of Halsted’s

procedure advocated removal of pectoralis minor muscle along with

pectoralis major. Cullen and William Welch was the first to do the

frozen session of the breast in the diagnosis of breast cancer.

20th century it became evident that cure can be achieved by

surgery. Halsted and Meyer surgery didn’t include supra clavicular and

internal mammary nodes and its removal did not show any improvement

in survival. William Handley showed the involvement of internal

mammary node when axillary node was involved in breast cancer

patients. Jerome and Owen Wangsteen advised supra radicle

Mastectomy which involved dissection of mediastinum and neck.

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Cushman Haagensen classified breast cancer according to size and nodal

status . He was the first person to advise breast self-examination. In 1948

the first concept of modified radical mastectomy was done by Patey and

Dyson. Donald Morton and Giuliano developed sentinel node biopsy

technique. In 1937 London surgeon, Geoffrey Keynes described minimal

surgery for breast cancer and advised radiotherapy which had equally

good result . In 1948 simple Mastectomy followed by radiotherapy was

introduced by R. McWhirter.

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Radiotherapy

Emile Grubbe medical graduate studying 2nd

year from Chicago

was the 1st person to irradiate breast cancer patients, he used tin foil to

protect the normal skin to protect the normal skin

In 1896 Hermann Gocht of Germany treated breast cancer patients

with radiation and used flexible led to protect normal tissue

In 1903 1st department of radiotherapy was founded by J.Pollock

in London George Perthes a surgeon from Germany described curative

effect of X- rays

Post op radiotherapy was used in America and Europe before

world war I. before world war I energy used was 150kv X-rays, after

world war II 170-200kv X-rays was used

In 1929 S. Harrington of the mayo clinic studied 1859 breast

cancer patients irradiated between 1910-1923. He expressed doubts

about ancillary RT George Pfahler from Philadelphia adviced post op RT

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for all cases of breast cancer after 2 weeks of surgery. In his review of

102 patients there is no significant benefit in survival in stage I patients

but showed a improved 5 year survival in stage II patients.

Radiotherapy as a single modality for breast cancer was used in in

operable cases during the beginning of 20th century until 1922.

William Stone from New York showed the benefit of RT over

surgery in inoperable breast cancer based on his experience on 10000

patients.

Geoffrey Keynes from London in 1932 used radium for

therapeutic use irradiation and showed 5 years survival rate of 77% in

node negative patients and 36% with node positive patients.

1930 super voltage X-rays were available .Francois Baclesse of

Paris did local excision of breast cancer followed by RT from 1937-

1953, and said that results were equal for stage I and stage II breast

cancer , between post op RT vs only surgery.

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In 1948 Robert McWhirter proposed simple mastectomy followed

by RT He said radical mastectiomy was over kill for stage I breast

cancer, but inadequate for stage II breast cancer.

1960 cobalt emerged

1970 linear accelerator emerged

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Chemotherapy

Paul Ehrlich was the father of chemotherapy.Arsenic was used in

ancient times for breast cancer treatment.

1898 1st alkylating agent was used.

World war II nitrogen mustard came into use .

1957 C. Heidel Berger used 5FU in breast cancer.

In 1958 thiotriethylenephospharamide alkylating agent.

1963 E.Greens Span used multi drug trials using methotrexate

with thiotepa.

Gianni Bonodona was the 1st person to start CMF regimen in

breast cancer.

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Hormone therapy

Hormone therapy in breast cancer patients was started even before

20th century in 1889- Schinzinger of Germany proposed oophorectomy

before mastectomy .

In 1896-1901 George Beatson advised oophorectomy for breast

cancer patients .

In 1900 Boyd was the 1st person to combine oophorectomy with

mastectomy.

In 1953 Charles Higgnes combined oophorectomy and

adrenalectomy .

In 1950s hypophysectomy was done for advanced breast cancer.

1939 P.Ulrich used testosterone for breast cancer .

In 1944 Alexander Haddow used synthetic oestrogen .

In 1938 Edward Dodds synthesized stilbesterol.

I.Naphasyn also synthesized stilbesterol .

In 1950-1960 oestrogen and androgens was used much.

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In 1973 W.McGuire demonstrated oestrogen receptors in breast

cancer patients .

In 1975 K.Horowitz demonstrated progesterone receptors.

In 1980 tamoxifen and SERM was used

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History of staging

Has a long history surgeons divided into two groups to decide on

surgery either inoperable or operable, on the basis of certain observations

staging was initiated .

Steinthall’s grouping

Group1

Group 2

Group3

In 1940 manchester classification consists of

stageI

stage II

stage III

stage IV

Portmann classification

In 1943 CCC(cloumbia clinical classification )evolved from

Haagensen and Stout’s

Stage A-D

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In 1954 UICC emerged started TNM classification developed by

Pierre Denoix of France

In 1962 AJCC emerged .Carcinoma breast is the most commonly

diagnosed cancer in women all over the world, affecting nearly 21% of

all cancer diagnosed in females a with high ratios in North America,

Western Europe, intermediate rates in South America and Eastern

Europe and low rates in Asia. 10 percent of newly diagnosed breast

cancer patients have metastatic breast cancer. After all treatments nearly

one third of patients will have progressive disease . metastatic breast

cancer median survival for the 3 yrs.

The range is very wide with some patients having more indolent

disease that they can live upto 10 – 15 years, while for others with

disseminated metastatic disease, the prognosis will be in the range of

months from the time of diagnosis. This will represent the disease extent

and distribution of metastatic disease, and reflects the biological

behaviuor of carcinoma of breast, while some women have disease

which shows good response to hormonal treatments, while others

with triple negative breast cancer can show increased resistance to all

systemic therapies.

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The aim of treatmentic breast cancer is to increase the symptom

free survival and increase quality of life . at the same time the side effect

of the treatment to be minimised. The treatment for metastatic breast

cancer is depends on the individual patient and receptor status, general

condition of the patient. Even with newer systemic and locoregional

treatment mestatic breast cancer cannot be cured at present.In few

pateints with good prognostic factor these treatment modalities increases

the progression free survival which inturn may significantly affects the

overall survival. Many patients with metastases may live several years

with modern locoregional treatment and systemic chemotherapy.

Regions No.of Cases CIR ASR

World 1676633 47.9 43.3

More Developed

Region

793684 124.1 74.1

Less Developed

Region

882949 30.9 31.3

India 144937 23.8 25.8

Chenai (09-10) 1568 34.2 35.7

Breast Cancer Statistics

Source: Globocan 2012,IARC Publications & MMTR Report

CIR: Crude Incidence Rate per 100000 Populations

TOTAL NO OF BREAST CASES IN CHENNAI IN THE YEAR OF

2012 - 1568

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NATURAL HISTORY AND ORIGINS

Concepts regarding the natural history of breast cancer have

undergone great evolution over the past 100 years, with a profound

impact on the management of these patients. The Halstedmodel was

based on an orderly progression to the regional lymph nodes and from

there to distant metastatic sites. Later another hypothesis was fully

demonstrated in both laboratory and clinical studies by Fisher,who

advanced the concept that breast cancer, as a systemic process involving

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host–tumor interactions, would not show substantial effects on survival

with variations in locoregional treatment.

A third hypothesis putforward by Hellmanconsiders breast cancer

as a heterogeneous disease with aspectrum extending from a tumor that

remains localized throughout its course to one that disseminates

systemically, even when detected as a small lesion, suggesting that

metastases are a function of tumor growth and progression factors.

BREAST CANCER RISK FACTORS

Established Risk factors,

1. Age of the patient

Early Menarche, late menopause, Age at first child birth( related

to estrogen exposure)

1. Duration of Breast feeding

Decreasing the breast cancer risk by delaying ovulation and

decreasing the hormone exposure

2. Height weight and body mass index

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3. Physical activity

4. Alcohol consumption

5. High dose estrogen containing oral contraceptive pills

And hormone replacement therapy in postmenopausal women

6. Inonizing Radiation

7. Family history and genetic susceptibility

Possible risk factor

1. Fat and future

2. Dietary phytooestrogen

Hereditary breast cancer

5-10% of the breast cancer is due to familial risk factor.

The breast cancer susceptibility genes divided into three types.

1. High penetrance

2. Intermediate penetrance

3. Low penetrance

Low penetrance are the most common variety BRCA1 and

BRCA2 genes Fifty percent of the familial breast cancers are mainly due

to BRCA1 and BRCA2 genes.

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This increases the relative risk of the cancer breast to 10 to 30

times of the normal population.

The prevalence is more common in jewish population. BRCA1

mutations characteristically has a basal – like phenotype, inactivating

germiline mutation. The similarity between hereditary BRCA1-related

sporadic BLBC sporadic basal like breast cancers may also harbor an

underlying defect in BRCA1, which has been termed “BRCAness”.

BRCA2 – related cancers do not have an association with TNBC or the

basal – like phenotype. Other rare breast cancer susceptibility genes

related to the breast cancer are CHEK2,TP53,PTEN,STK11

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DISTIBUTION

Upper outer quadrant is the most common site of carcinoma breast

which contributes about 38% of the total incidence. The second common

site is the central area of the breast followed by upper inner quadrant and

then the lower inner quadrant.

The distribution correlates with the difference in density of breast

tissue in various quadrants.

LOCAL SPREAD

During the development and progression of the breast carcinoma,

it starts from the ducts and then breaches the basement membrane enters

into the surrounding breast parenchymal structure. The tumor can grow

through the wall of blood vessels, spread into the deep lymphatics of the

dermis, and eventually produce edema of the skin (peaud’orange), which

usually indicates that the superficial as well as the deep lymphatics are

involved. Skin dimpling can be caused by involvement of Cooper’s

ligament. Ulceration and infiltration of overlying skin, which may

22

develop late in the course of the disease, are usually preceded by fixation

and localized redness of the skin over the tumour.

Axillary Spread

Majority of the breast carcinoma spread through axillary nodes

and the percentage of the nodal involvement increases with tumour size.

The percentage varies from between 10% and 40% depending on the size

of the tumour.

Supraclavicular Spread

Spread to supraclavicular lymph nodes usually follows

involvement in the high axillary lymph nodes or IMNs. Clinical failure

in the supraclavicular fossa is relatively rare in patients with early-stage

breast cancer and is dependent on the degree of axillary involvement.

For patients with no or minimal nodal involvement (less than three

involved axillary nodes), supraclavicular failure is extremely rare.

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Internal Mammary Spread

Metastases to the internal mammary nodes (IMNs) are correlated

with tumour size, are more frequent from medial half and central lesions,

and occur more frequently when there is axillary node involvement

Systemic Spread

Of the systemic metastasis,

Approximately 60% are in bone,

10% in lungs,5% in liver,

5%in central nervous system

15 to20% in multiple sites.

ANATOMY

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The female breasts are modified eccrine glands on the anterior

chest wall, superiorly frim the second rib to inferiorly upto the 6th

rib,

medially to the sternal edge and laterally upto the mid axillary line. The

breast parenchyma is composed of lobules and ducts. The function of the

lobules is to produce milk and the function of the ducts is to transport

lactation products to the nipple The breast parenchyma is intermixed

with connective tissue, which has a richvascular and lymphatic network.

Mammary gland lymphatics begin in the interlobular or prelobular

spaces, follow the ducts, and end in the sub areolar network of

lymphatics of the skin.

Lymphatic drainage of the breast

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The predominant lymphatic drainage of thebreast is to axillary

lymph nodes,The level I axilla iscaudal and lateral to the muscle, level II

is beneaththe muscle, and level III is cranial and medial to

themuscleLymphatics can also drain directly into theinternal mammary

lymph node chain (IMC), whichareintrathoracic structures located in

theparasternal space. Although these nodes are notusually visualized on

computed tomography (CT),the anatomical region of the IMC can be

determinedby the internal mammary artery and vein, which areeasily

visualized by CT (Fig. 56.3 ) and usually lie3 to 4 cm lateral to midline

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PATHOLOGY

Breast carcinomas are divided in to insitu carcinoma and invasive

carcinoma

Insitu carcinoma are divided into ductal carcinoma insitu and

lobular carcinoma insitu.

INVASIVE CARCINOMAS

The histological typing of breast cancer is made by exclusion

INVASIVE DUCTAL CARCINOMA (NOS) is an invasive carcinoma

that doesn’t fulfil definition of other categories.

Invasive lobular carcinoma, tubular carcinoma, mucinous

carcinoma, cribri form carcinoma, papillary carcinoma, scirrhous

carcinoma, comedo and medullary carcinomas are fuse specified types of

breast carcinoma. Histological used in the Brest cancer is proposed by

elston and ellis it is the modification of bloom rich at son in 1957 it has 3

factors

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1. Tubule formation

2. Pleomorphism

3. Mitotic activity

Each factor scored on a scale of 1-3 tubule formation Histological

grade

3 – 5 - well differentiated tumours

6 – 7 - moderately differentiated

8 – 9 - poorly differentiated

Luminal A

100% ER positive,70% ER positive, good risk , 10 years relapse

free survival 70%, low risk on oncotype Dx and Mamma print and

hormone responsive tamoxifene responsive ,chemo insensitive ,Ki 67%

<14% primary tumor 62% T1 , 38% T2 , HER2 negative ,

Luminal B

ER positive less than 50%, PR positive bad prognosis , 10 years

relapse free survival 53% ,tamoxifene insensitive , aromatase inhibitor

sensitive , Ki 67% more than 14% ,younger age higher grade , 30% are

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HER2 positive ,Intermediate to high risk on oncotype DX and Mamma

print

Basal type

Do not express ER,PR or HER2 negative 85% (triple negative) are

basal

Express myoepithelial cell membrane CK5 , C-Kit ,EGFR, HER2

tends to be high grade .

NG-III, present with large tumours T2 and above

chemoresponsive high relapse rate in CNS

BRCA1 tend to be basal line common in African Americans

Angiogenesis

Targeting angiogenesis in metastatic breast cancer Judah Folkman

in 1970 first described the concept of angiogenesis by targeting blood

vessel formation by preventing tumour growth and metastasis . he

defined anti angiogenesis therapy which causes regression of tumour by

altering tumour vasculature , normalization of surviving tumour

vasculature , inhibition of regrowth of vessel and neovascularisation in

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tumours, eg. antiVEGF antibody-Bevacizumab dose:10mg /kg every

2weeks of 15mg /kg every 3weeks

Prognostic bio marker

Indicates the proabablity of specific clinical outcome such as

recurrence progression survival independent of treatment

Predictive bio marker

Indicates the chance of response to specific therapy

Response indicator

Monitors response and assist in stop vs continue treatement

Pharmacokinetic bio marker

It measures pharmacokinetic parameters of drug exposure

Pharmacodynamic bio marker

Measures end point of drug effect on target pathway and

downstream biological process

Prognostic multigenes signatures in carcinoma breast

Mamma print –microarray-70genes –freshfrozen tissue

Rotterdam signature-microarray-76 genes-freshfrozen tissue

Genomic grade index-microarray-97genes-freshfrozen tissue

Mammostrat IHC-5genes-Formaline embedded fixed paraffin

30

Oncotype DX –qRT-PCR-21 genes- Formaline embedded

fixed paraffin

DIAGNOSTIC EVALUATION

History

Complaints related to the breast cancer and history related to the

risk factors to be elicited history of any lump in the breast, nipple

discharge, skin changes, any axillary swellings to be asked.

Physical examination

It includes inspection and palpation of the breasts, axilla,

supraclavicular region,

The breast is examined by various positions including sitting with

arms either side, sitting positions with arms above the patient’s head,

patient’s hands pressed against her hips the following changes in the

breast to be noted

1. Any asymmetry of the breast

2. Inverted nipple

3. Skin changes

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Palpation of breast.

It should be perform with the patients in supine position and also

in sitting position

Signs of breast cancer.

1. Palpable mass

2. Nipple discharge- unilateral bloody discharge

3. Nipple changes – any retraction, infiltration, pagets .

4. Skin changes – dimpling or skin retraction.

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Biopsy

The following important factors to be identified in the specimen

which is needed for further management.

Hormone receptor status – ER,PR status

1. HER2 neu status

2. Histological type of cancer

3. Histological grading

Baseline investigations

1. Complete blood count

2. Blood biochemistry

3. Liver function test

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4. Renal function test

5. X ray chest PA view

6. Ultrasound abdomen and pelvis

7. Ct chest

8. Bilateral mammogram.

MAMMOGRAM

Mammogram provides additional information

In the presence of palperable mass mammography is useful in

detecting occult lesion in same or opposite breast, it is classified as

screnning mammography of diagnostic mammography

Screening mammography to screen asymptomatic women

Diagnostic mammography is a definite imaging workup to locate a

mammographically visible lesion

IMPORTANCE OF MAMMOGRAPHY IN BREAST CANCER

Reduction in breast mortality

Swedish country trial 30% (40-74 years)

Malmo trial 36% (45-49 years)

Gottenberg trial 45% (39-49 years)

Metaanalysis of 5 swedish trials 29% (40-59 years)

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TYPE OF VIEWS

In screening mammography –two views, mediolateral oblique

view and cranio caudal view

In diagnostic mammography – mediolateral view craniocaudal

view and exaggerated CCL –CCM

MAGNIFICATION VIEWS

BI-RADS ( british imaging reporting and data system) false

negative 75-80% due to dense breast in young women

Classification

Category 0 – assessment incomplete used in screening

Category 1 – normal

Category 2 – benign finding

Category 3 – benign probably

Category 4 – malignancy suspected

Category 5 – malignant

What is triple diagnosis?

Physical finding

FNAC

Mammogram

35

WHAT IS A MASS?

M –mobility T – tenderness

A –attachement L - location

S –shape C - consistency

S – size

DEFINED AS A PALPABLE ABNORMALITY DISTINCT FROM

SURROUNDING TISSUE

USG of breast

USG of breast is a useful complement to mammography for

evaluation of dense breast when results of physical examination and

mammography are equivocal useful in these group of patients

1. Those with dense breast and localized sysmptoms of with a

suspicious area detected in MMG

2. Those with non palpable abnormality discovered on MMG

3. Those with palpable masses considered intermediate on MMG

4. To guide aspiration of non palpable cystic structure

5. To do FNAC of small lumps

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MRI of breast

Sensitivity 97-99%

Specificity 28-37%

Greatest strength of MRI to detect occult metastasis in dense

breast and recurrence after irridation

FDG PET scan

Sensitivity 93%

Specificity 73%

Accuracy 89%

Positive predictive value 92%

Negative predictive value 96%

False negative 20%

Bone scan: technetium 99, F18 – more specific recommended for

stage II and above cancers and T size >2cm

The mammographic findings for malignancy include ill definded

mass with spiculatlions, micro calcifications (100 to 300 um rod like,

tubular, branching or punctuate) and architectural distortion.

Magnetic Resonance Imaging

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Indications

To assess the silicone implant integrity

To diagnose the malignancy in reconstructed breast

To rule out multifocal disease before doing Breast reconstructive

surgery

To assess the response to neoadjuvant chemotherapy

To diagnose the occult primary.

Positron Emission tomography The metabolism of the tumour

cells are mainly by glycolysis not by oxidative metabolism

This difference between tumor cells and normal cells is the basis

for the PET imaging.

Uses

1. To differentiatiate the recurrent breast cancer from postoperative

scar.

2. Have high accuracy in detecting presence or absence of lymph

node involvement

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3. Able to screen the whole body in a single imaging method for

distant metastasis

4. Pet is very much useful in the quantitative response assessment

after neoadjuvant chemotherapy.

STAGING (TNM CLASSIFICATION) AJCC 2010

Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 mic Tumor</=1 in greates dimension

T1a Tumor>1<5 mm in greatest

dimension

T1b Tumor>5<10 mm in greatest

dimension

T1c Tumor>10>20 mm in greatest

dimension

T2 >2<5cm in greatest dimension

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T3 >5cm in greatest dimension

T4a Extension to chest wall not including

pectoralis muscle

T4b Ulceration and/or ipsilateral satellite

nodules and/or edema (including

peau d’ orange) of the skin

T4c Both T4 a and T4b

T4d Inflammatory carcinoma

Nx Regional lymph nodes cannot be

assessed

No No regional lymph nodes

N1 Metastases to movable ipsilateral

axillary lymphnodes(s)

N2a Metastases in ipsilateral axillary

lymph nodes fixedto one another

(matted) or to other structures

N2b Metastases only in clinically detected

ipsilateral internal mammary nodes

and in the absence of clinically

evident axillary lymph node

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metastases

N3a Metastases in

ipsilateralinfraclavicular lymph node

(s)

N3b Metastases in ipsilateral internal

mammary lymph nodes (s0 and

axillary lymph node (s)

N3c Metastases in ipsilaternal

supraclavicular lymph node(s)

M0 No distant metastasis

M1 Presence of distant metastasis

COMPOSITE STAGING

STAGE 0 Tis No Mo

STAGE1A T1 No Mo

STAGE1B To N1 mic Mo

STAGE2A T1 N1 mic Mo

STAGE2B T0 N1Mo, T1 N 1 Mo, T2 No Mo

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STAGE3A T0N2Mo, T1 N2 M0, T2 N2 M0

T3 N1 M0, T3 N2 M0

STAGE3B T4 N0 Mo, T3 N1 M0 T4 N2 M0

STAGE3C Any T N3 M0

STAGE4 Any T Any NM1

Overall survival of breast cancer patients correlates with the stage

of diseae at presentation. The table depicts 5 years survival according to

stage of the disease”

Stage 5 Year Survival

0 100%

1 98%

2A 88%

2B 76%

3A 56%

3B/C 49%

4 16%

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METASTASES:

The metastatic potency of cancer cells depends upon the intrinsic

properties of tumor and their interactions with tissue environment. The

steps of metastases include Proliferation of tumor cells by paracrine

growth (tissue environment), autocrine growth (from tumor itself)-

EGFR, c-erb /HER2neu, TGF- alpha, HRG, Neovascularisation due to

new vessel formation by factors released by the tumor and tumor cells

exhibit motility there by detachment and movement from the primary

site

Invasion is a process by which there is destruction of basement

membrane, connective tissues, adhesion and motility with response to

release of factors.Distant metastases is due to release of cancer cells in to

blood or lymphatic stream in to the body as single cell or emboli . These

emboli gets arrested in the draining sites like lymph nodes ,organs

,adhere to endothelial cells and capillary beds. Extravasation also

involves same steps of invasion 8) Growth in the deposited organ of

metastases depends upon the responses of paracrine and auto crine

factors of the tumor,once metastases establishes it becomes a source for

further metastases known as “ METASTASES OF METASTASES”.

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The risk of relapse in carcinoma breast patients is more during the

first 2 yrs after diagnosis and treatment, the time of events and survival

of cells vary in circulation within minutes to years.

Genes associated with metastases in carcinoma breast are

S100A4/MTA-1/ Osteopontin /bcl-2/maspin.Genes associated with

suppressing of carcinoma breast are nm23/ KAI1 /KiSS 1/BRMS1.

Metastases in breast cancer was described by Stephen Paget base on”

seed and soil “hypothesis .

Role of surgery in metastatic breast cancer

At present carcinoma of breast has replaced carcinoma of cervix in

Indian tumor registries. Survival of these patients has increased over the

years. Over the years systemic therapy is the treatment of chronic and

local therapy like Radiotherapy and Surgery.

Mechanism of Metastases in breast cancer

Halsted was the first person to state the therapy of metastases.

According to him breast cancer is a localized disease in the breast and it

44

spreads to axillary nodes and to the sanctuary site. Hence he advocated

extensive loco-regional treatment.

Bernard Fischer later defined that breast cancer was a systemic

disease, which has a capacity to spread to other sites even before

diagnosis. Later Spectrum theory emerged and stated that exact meaning

of metastases to distant sites was unclear. Hence advised both systemic

and local therapy.

STEPS IN METASTATIC PROCESS

45

Lang et al described three theories

1. Parallel evolution, which says that circulating tumor cells present

in the tumor is the cause for the metastases during tumorigenesis

even before the development of the intact primary tumor.

2. Gene expression profile theory says that potential for metastases is

an inherent property genetically present in breast cancer patients

during early stages

3. Stem cell model says that metastatic potential of breast cancer or a

specialized tumor initiating cancer cells.

Danna et al defined the concept of surgery in metastatic breast

cancer by the theory of immune-suppression, which is reversible by the

surgical removal of primary tumor. The first study in evaluating the

treatment of metastatic breast cancer was by Khan et al in 2002, which

was a retrospective study, which showed survival benefits.

Survival benefit?

Question to be answered before initiating the treatment.

At present survival for visceral metastases is 6 months, nodal

disease is 18 months, bone only disease is 3-4 years.

46

In Khan et al study which reviewed NCDB, 3 years survival was

24.9% for the whole group. Survival for total Mastectomy 31.9 months,

partial mastectomy 26.9 months, no surgery 19.3 months .

There are several studies which showed survival benefit like

Rapids et al, Gnerlich et al, Blanchard et al, McGuire et al , Babiere et al

, Neuman et al, reported trends towards increased survival. But it was not

statically significant.

Should lymph node dissection be done?

The exact details are not reported not so far in most of the reviews.

When the logic of improving the survival applies to removal of the

primary, the same can be applied to ALND. Hence patient under going

total Mastectomy can be given the benefit of ALND. NCDB conclude

that ALND can be a contributing factor for survival with total

mastectomy but it is an independent prognostic factor. Studies evaluating

the benefit of ALND are Rapids et al, McGuire et al and Neuman et al.

All these studies showed some survival benefit and advised ALND as a

part of treatment approach.

Negative margin be attempted?

47

Even though negative margin is the fundamental concept of

oncology, there is a lack of data towards the role of negative margin

resection in metastatic breast cancer. The studies evaluating this are

Rapids et al, McGuire et al and Khan et al. These studies supported the

need for negative margins based on the review, which showed five-year

survival of 27% for negative margin, 16 % for positive margin and 12 %

for unknown margin. Hence it will be better to give negative margin.

When to operate?

When the decision of loco-regional treatment is offered, then the

timing of the surgery is to be decided. Based on the review of articles

showed that surgery may be done after three months of initial

diagnosis/chemotherapy improved progression free survival. The time

gap between diagnosis/ chemotherapy makes the oncologist to study the

behavior of the disease. Studies favoring this are Babiere et al, Neuman

et al, and Rao et al.

Prospective Trials

48

The MF 07-01 9(NCT00557986) is phase 3 RCT that compares

metastatic breast cancers patients at presentation who receive loco

regional treatment Vs no treatment and to assess the overall survival

benefit, which was activated in 2007. Short interim remits in ASCO

2010 shows no evidence for surgery. Similar NCT 00193778 study from

India familiar to show such benefit.

The current evidence is not enough to use surgery for primary

MBC. However there is subset of patients who may be offered loco-

regional treatment such as surgery to maximize survival.

CONCURRENT CHEMOIRRADIATION

There is no enough dsatafavouring concurrent chemoirradiation in

locally advanced breast cancer and metastatic breast cancer ,but there are

studies favouring concurrent chemoirradiation in breast conservation

surgery even though not practiced much.Studies favouring concurrent

chemoirradiation are the following.

Study1: Argangelia et al did randomized study using concurrent

Vs sequential CMF chemotherapy.

49

Sample size 206 pts,TD 50Gy/20# over 4 wks followed by 10-15

Gy electron boost following BCS.there was no difference in breast

recurrence, metastasesfree ,diseasefree ,overall survival in the two

treatment. all patients completed the total dose of Rt and there was no

difference in toxicity profile between the two arms ,study showed that

RT can be delayed for 7 months if margins were negative and considered

concurrent CMF as a safe regimen and may be used in patients with

high risk of local recurrence.

Study2:Rousse et al study used FNC regimen consisting of Inj

5FU 500 mg/m2 / Mitoxantrone 12mg/m2/ Cyclophosphamide

500mg/m2 to sequential FEC regimen consisting of Inj2FU200mg/m2/

Epiribicin 60mg/m2/ Cyclophosphamide 500mg/m2.

Sample size 650 pts RT in node positive breast cancer

ptspts.There was no difference in DFS or overall survival(3% Vs 7%)

out these 6 had LRR in concurrent arm and 18 had LRR in sequential

arm.

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Study3: Tolenado et al studied Arm –A sequential chemo +RT,

Arm B concurrent chemo irradiation using FNC regimen consisting Inj

5FU/Mitoxantrone/Cyclophosphamide. Sample size 214 pts,local control

was superior in concurrent arm but toxicity was more like subcutaneous

fibrosis/ telangiectasia /skin pigmentation /breastatrophy.but there was

no difference in Grade II skin reaction/breast pain/lymphedema

Study4: Calais et al similar to Rousse et al study .Toxicity was more, LC

was good/LRR was low.

Study5:Bellon et all: was prospective single arm study which

showed good local control in high risk group patients with

le received concurrent CTRT 109 ptsVs 426 pts received sequential RT,

local control and locoregional relapse was lesser in CTRT arm ,these

studies did not use Adriamycin and taxanes.

Study7:Goyal et al studied using Bevacizumab in

combinatconcurrentCMFand lesser dose of RT.

Study:Rerospective study from Yaion with whole breast RT Vs RT alone

there was no difference in grade III reactions/no fatigue of RT/RT

fibrosis/ pneumonitis / lymphedema between the two arms.

51

HYPOFRACTIONATED WHOLE BREAST IRRADIATION

It is growing trend at present which involves delivering higher

dose per fraction with in a short period of time to a biologically

equivalent dose .START Trial A -1-( pT1-3a pN0M0)-TD:50 Gy25#Vs

41.6Gy or 39Gy in 13# of 3.2Gy or 3.0Gy over 5weeks after surgery.

Over all treatment time was kept constant in all three arms including

SCL& Axilla. Primary end point was LRR .LRR at 5 yrs was 3.6% for

50 Gy/3.5% for 41.6Gy/5.2% for 39 Gy.START B Trial- (pT1-3a pNo-1

M0)-TD 50Gy25#/40Gy 15# of 2.67 Gy over 3 weeks .Here over all

treatment time was not consistent.LRR at 5 yrs was 2.2 % for 40

Gy/3.3% for 50 Gy. Whelan et al study after BCS randomized to TD:50

Gy @25# vs 42.5 Gy@ 16#.LRR at 10 yrs was 6.7% for 50 Gy 25

#/6.2% for 42.5 Gy 16 #.

ASTRO 2011 concluded that hypofractionated whole breast

irradiation is equivalent to conventional irradiation who meet the

following criteria 1)50 yrs and above 2)pathologicT1-T2 N0 treated with

lumpectomy 3)patient not receiving chemotherapy 4)minimum and

maximum dose along central axis not <93% and not >107%.heart should

be excluded from treatment fields during planning hypofractionated

52

RT.RTOG 1005 is phase III study on hypofractionated RT.Taking

age/comorbidities/distance of RT facility in to consideration

Hypofractionated RT may be offered to these patients. Accelerated

Partial Breast Irradiation :

Even though whole breast irradiation is the standard of treatment

for BCS patients APBI is an alternate approach which can shortern

treatment time ,there by more easier for patient,easier delivery of

radiation and chemotherapy ,also reduces the treatment cost.

The concept behind this approach is that much of recurrences

occur at near the operated site.

This modality includes multicatheter interstitial implants which is

placed around the operated site, Mammosite technology which uses

single ballon catheter in were in a radiation source is afterloaded at the

operated site ,external beam conformal partial breast irradiation and

intraoperative single dose irradiation.

This modality has not yet under a randomized study to prove it is

equivalent to whole breast irradiation . The current study under trail is

NSABP-39/RTOG-0413 which allows one of three APBI techniques.

53

Multicatheter Interstial Techniques: This modality includes tumors

< 3 cm after lumpectomy,negative margins,0-3 nodes positive,no

ECE.Dose LDR APBI-45 Gy in 3.5 t0 5 days or HDR APBI 34 Gy in 10

BD # with in 5 days.No significant adverse effects was noted,No

statistically significant ipsilateral breast recurrences, or

LRR,OS,DFS.Studies evaluating APBI are Kuske et al , Vicini et al

,Arhur et al ,Wazer et a ,

Mammosite:More extensively used in America,this contains a

catheter with a central ballon inflated at the lumpectomy site,the distance

between ballon and skin is > 5mm or ideally >7 mm,treatment is

delivered by HDR remote after loading system with 1 cm circumference

around the tumor.Dose 3.4 Gy at 1 cm twice daily to atotal dose of 34

Gy over 5 days.It was said that treatment benefit,cosmetic effect,toxicity

at 5yrs using Mammosite was similar to other forms of APBI.

54

APBI (Accelerated Partial Breast Irradiation)

External Beam Conformal Radiation.

At present over 70 percent of breast cancer patients being treated

with 3D-CRT which is totally non invasive with homogenous dose

delivery and distribution.Dose 38.5 Gy at 3.85 Gy/# delivered daily CTV

included operated site + 1-1.5 cm clearance and 5 mm within the skin

surface and chest – lung interface.

Intraoperative Accelerated Partial breast Irradiation:radiation dose

is delivered using single intraoperative dose to the operative site at the

time of surgery using intraoperative electrons or intra operative

photons.Dose-20 Gy.

ASTRO 2009 consensus for APBI-patients > 60 yrs/node

negative/invasive ductal tumors <2 cm/negative margins/ER+/no LVSI.

55

Bone metastasis

Bone is the most common site of metastatic disease in the breast

cancer and affects up to 70% of women with metastases. Matastasis

occurs mostly in the axial skeleton.

Aim of Of treatment in bone metastasis is avoid skeletal related

events.median survival after bone metastasis is 19-25 months. if a

pathological fracture occurs it is reduced to 12 months.

Sometimes survival may prolonged with good risk factors like low

grade tumours, bone disease at initial presentation, long disease free

survival, hormone receptor positive . Bone-only disease has a better

prognosis than disease associated with visceral involvement.

Treatment for metastatic breast cancer with bone metastasis is

mainly hormone therapy therapies and bisphosphonates Radiotherapy

plays a major role in the treatment of bone metastasis as a palliation. . It

is of particular benefit for those patients with painful bone disease or

56

spinal cord compression and even in the face of a large burned of

metastatic disease due to the high response rate and low toxicity.

EFFECTS OF RT ON BONE:

The majority of bone destruction is meditated by osteoclasts,

which are in turn influenced by humoral factors released by thetumor.

Malignant stimulation of the RANK signaling pathway increases the

osteoplastic activity . New bone formation is predominantly reactive ,but

may be exuberant, generating new bone that often lacks the strength of

normal lamellar bone.

Pain may be either nociceptive (mediated by prostaglandins,

substance P, and other cytosine’s) or neuropathic (as a result of bone

destruction and increased resorption, peri-osteal irritation and nerve

entrapment). The mechanism by which radiotherapy improves pain is not

clearly understood.

Progression

Either an increase in worst pain score of 2 or more at the treated

site without reduction in analgesic use or an increase of 25% or more in

57

daily oral morphine. Equivalent compared with baseline without a

reduction in baseline worst pain score.

Fraction in the treatment of localized bone metastases

The largest single randomized study – the Dutch bone metastasis

study (DBMS) (13) – randomized only 29% of eligible patients. All of

the randomized studies included multiple different tumor types, but in all

cases breast and/or prostate cancer formed the predominant patient

groups. In the DBMS, 49.7% of the 1157 patients had breast cancer.

A single fraction of 8Gy delivered for palliation achieves a 60%

response rate by intention-to-treat analysis. Approximately one-third of

patients treated have a complete pain response. Overall, mean time to

response is 3 weeks and mean duration of remission is 18 weeks. Single

fraction are clearly more convenient for the patient and increase

treatment capacity for the radiotherapy center. While single fractions are

commonly employed in the United Kingdom and Canada, fractionated

regimens such as 20gy in 5 fractions or 30Gy in 10 fractions are the

norm in the rest of the world.

58

Re-treatment of bone deposits

Re treatment after a single fraction is recorded for 21.5% of

patients as compared with 7.4% of those receiving multiple fraction.

Single-fraction treatment has also been tested against multiple fractions

in the treatment of neuropathic bone pain, where it has been argued that

multiple fractions are required to required to reduce tumour mass and

relive pressure on nerves .

Axial metastasis

Presentation in the descending order in carcinoma breast

1. Vertebra primarily thorocolumbar

2. Pelvis

3. Ribs

4. Femur

5. Humerus

6. Other sites eg.scapula,tibia,skull

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Spinal metastasis

30-70% of patients with carcinoma breast has spinal metastasis at

the time of death

Pain in spinal metastasis is due to release of local chemical

mediators subatance P , bradykinin and histamine and due to enlarging

tumour mass, bone defect leading to pathological fracture /deformity

kyphosis /scoliosis or both ,nerve root compression due to tumour mass

,compression of spinal cord due to tumour mass because of tissue

reaction or fractured fragments

MANAGEMENT OF SPINAL METASTASIS

Class I –no nerve involvement –chemotherapy or local RT

Class II –involvement of bone no collapse – chemotherapy of local RT

Class III – neurological involvement –without body involvement –local

RT/steroids

Class VI – vertebral collapse with instability without nerve involvement

– surgery

Class V – vertebral collapse with nerve involvement – surgery

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Goals of spinal surgery should include neural decompression,

spinal stability, correction of spinal deformity

However with the advent of minimally invasive spinal surgery it is

concentrating on three main areas , biopsy , replacing bone loss by

vertibroplasty and kyphoplasty , reconstruction and stabilization through

endoscopic procedures

MANAGEMENT OF ACETABULAR METASTASIS

Class I –lateral cortex - superior medial walls intact – cemented THR

Class II – deficient medial wall – protrusio cup cemented THR

Class III – deficient lateral and superior wall – protrusion cup with

fixation with cemented THR

Class IV – solitary metastasis resection of lesion – girdle stone saddle

prosthesis of custom made prosthesis

Mirel’s scoring system for appendicular metastasis

Location –peritrochantric (3) – lower extremity (2) – upper extremity(1)

Lesion type – lytic (3) -mixed: lytic & blastic (2)- blastic (1)

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Amount of cortical loss ->2/3 (3) – 1/3 to 2/3 (2) - <1/3 (1)

Pain - functional (3) – functional, moderate(2) – moderate (1)

A score of 8 and above is indicative of surgery 30 -50 %of loss in bone

mineral density has to occur to be picked up on a plain X-ray film >50%

loss in thickness of cortical bone in plain X- ray signifies impending

fracture and osteolytic lesion >2.5cm is considered significant

CHARESTESTRICS OF METASTSTIC TNBC

TNBCs have a poor prognosis in the adjuvant setting,

characterised in particularly by early recurrence compared to other

subtypes of breast cancer. This occurs despite a high sensitivity to (neo)

adjuvant chemotherapy. Although cancers that have a pathologic

complete response (pathCR) to neoadjuvant chemotherapy have a good

prognosis, those cancers that donotachive a path CR have a marked poor

prognosis sith frequent and early relapse. Distance disease free survival

at 4 years was 87% for those who had a path CR compare to 69% in

those who didnot.

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A vast majority relapses from TNBC occur in the first 5 years

following prognosis the reasons for poor prognosis in the metastatic

setting are multi factorial. This reflects the lack of targeted therapies for

TNBEC and the highly proliferative nature of TNBC this reflects the

pattern of metastasis seen in TNBCs characterised by less frequent bone

and liver metastasis and more frequent lung and brain metastasis.

Current evidence suggests that triple negative basal like and non basal

like breast cancers have similar pattern of metastasis

Molecular subtype is also predictive for risk of loco regional

recurrence after these breast conserving surgery and mastectomy with

contemporary trastuzumab containing adjuvant systemic therapy the

outcome of the HER2 enriched group is now likely to have improved

,leaving BLBC as the cancer subtype with highest risk of local relapse.

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LEPTOMENINGEAL METASTASES:

It is commonly seen with lobular histology of carcinoma breast

,it arises mostly from the pia and archanoid space or subarachnoid space

,spread is due through blood ,direct extension through venous plexus

along nerves or perineural invasion .Once it reaches the meninges it

spreads through CSF. Symptoms will be due to raised ICT ,local

inflammatory responses like severe headache and vomiting ,focal

neurological deficits,seizures.Investigation of choice will be Gadalinium

enhanced MRI, prognosis is poor ,survival will be 5-7 months.

Radiotherapy to craniospinal axis is difficult due to bone marrow

toxicity. Intrathecal chemotherapy and systemic chemotherapy is

advised in these conditions.

INTRA MEDULLARY METASTASES:

One of the rare presentation in breast cancer 0.1-6%, overall

survival 13 months .commonly involves cervical spine. Clinical signs

depends upon the level of involvement. Investigation of choice is MRI

64

(iso intense and nodular on T1 images and pencil shaped hyper intense

on T2 images .Treatment involves steroids and radiotherapy.In patients

with stable disease and without leptomeningeal spread surgery can be

attempted.

EPIDURAL METASTASES:

The most vascular portion which is the posterior part vertebral

body is the site of metastases, commonly involves thoracic vertebra(50-

60%),lumbar (30-35%),cervical(10-115%)in proportion to the volume of

bone marrow . Back pain is the most common symptom ,myelopathy due

to spinal cord compression , sensory disturbances. Investigation of

choice will be MRI ,plain X-ray may be useful to see the stability of

spine .

Goal of treatment

1. preserve neurological function

2. relieve pain

3. preserve stability of spine.

65

Conservative treatment includes inj dexamethasone, radiotherapy

with one level above and one level below. Surgery involves

laminectomy and spinal stabilization followed by post op RT after 3

weeks. Surgery may involve anterior or posterior decompression .Recent

advances in treatment involves procedures like vertebroplasty or

kyphoplasty .

“To cure sometimes To relieve sometimes To comfort always .”

TREATMENT

Carcinoma Breast has been divided into Early stage, Locally

advanced and metastatic breast cancer. Treatment options vary

according to the stage of the disease. The surgical management of breast

cancer improved a lot for the past 30 years. Inially according to

Halsteadian principles aggressive surgical management was done by

Classical radical mastectomy.

Another hypothesis suggested that the extent of surgical resection

alone not sidnificantly affect patients outcome and this supported bt

trials also. As a result administration of poatoperative systemic

66

chemotherapy, hormonal therapy or both become standard practice for

the majority of the patients. It reduces the rate of recurrence and

metastasis ,so increases the overall survival. So surgery may be

modified radical mastectomy or breast conservative surgery.

Neoadjuvant chemotherapy plays a major role in locally advanced breast

cancer to make the inoperable tumors to operable one. Even in operable

tumorsneoadjuvant therapy is used before breast concervative surgery.

SURGERY:

The surgical management of patients is involves both the primary

tumor and regional lymphatics. The primary tumor may be managed by

modified radical mastectomy or Breast conservative surgery .Axilla is

treated by either axillary dissection or sentinallymphnode biopsy.

CHEMOTHERAPY

SCIENTIFIC RATIONALE for primary systemic chemotherapy

The role of is primary systemic chemotherapy or neoadjuvant

chemotherapy was justified by several hypothesis.it indicated that non

67

courative reduction of tumor cell burden increased the

proliferaticells.after surgery of the primary tumoue there is an increase in

the proliferation of remaining tumour cells in the metastatic sites. This

change occurs even after primary tumour irradiation. Removal of a

primary tumor exerts its affect over the metastatic sites and causes

stimulation of growth following surgical removal or reduction was due

to soluble growth factor..

The neoadjuvant chemotherapy helps to decreases the

micrometastases and prevent cancer growth cyclophosphamide,t

amoxifen and radiotherapy prior to surgery prevent kinetic alterations

suppresses tumor growth which inturn may increase the survival.

The Goldie – coldman hypothesis

As tumor cell population increases, an ever expanding number of

duly resistant phenotypic variants arise time to spontonous somatic

mutations that become more difficult to eradicate. The resistant cells

can be minimized by initiating combination of non cross resistant drugs

when the tumor cells are less in number. when the tumor grows not only

the number of resistant cases increases and so is the proportion of

resistants cells in the total cell population. Resistant phenotypes

68

multiply not only as a results of their own intrinsic growth rates and also

due to the addition of new mutation.

Increased proliferation of cells following surgery causes increase

in the number of resistant phenotypes in the metastasis. Neoadjuvant

therapy not only stop cell proliferation but also eliminate cells that would

have been made more sensitive by their kinetic alteration following

surgery.

Scientific rationale for adjuvant chemotherapy

Skipper and schabelconcept

They proposed that growth fraction and doubling times of tumors

differs in from those in micro metastasis. So later they may well respond

to adjuvant chemotherapy. After the primary surgery with decrease in

tumour burden may alter the growth charecteristics and increase the

chemosensitivity of the adjuvant treatment. It justifies the adjuvant

chemotherapy.

69

Adavantages of neoadjuvant chemotherapy

1. Chemotherpay response can be assessed in vivo

2. Downstaging of the primary tumour and nodes.

3. Feasibility of surgery is enhanced due to reduction in tumour

growth

4. Response to the chemotherapy act as a prognostic factor for long

term survival.

Disadvantages of neoadjuvant chemotherapy

1. It delays the effective primary therapy

2. Imprecise clinical and radiological staging

3. Loss of prognostic significance of axillary nodal statusUnknown

relevance of surgical margin

4. Large no of drug resistant cells may present

5. Response to the primary tumour may not correlate with the

response to the micrometastasis

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Antracycline and Taxane based chemotherapy regimens are

currently the most effective agents for women with locally advanced and

operable breast cancer. The most recent Eastern Breast Cancer

TraialistsGroup(EBCTCG)results published in 2005 concluded that

treatment with approximately 6 months of anthracycline-based

chemotherapy with a regimen such as 5-fluorouracil, Adriamycin, and

Cyclophosphamide (FAC) reduces the annual breast cancer death rate by

about 38% for women younger than 50 years of age and by about 20%

for those of age 50 to 69.

71

This meta-analysis also confirmed a moderate but highly

significant advantage for anthracycline-based regimens (those including

Adriamycin or Epirubicin) to regimens consisting of Cyclophosphamide,

methotrexate, and 5-fluorouracil (CMF) in trials involving more than

14,000 patients. The Cancer and LeukaemiaGroup(CALGB) 9344 study

randomized 3121 women who had node-positive breast cancer to four

cycles of AC or four cycles of AC followed by four cycles of Paclitaxel

(AC-T) with dose-escalated doxorubicin. The addition of Paclitaxel was

associated with significant 5-year DFS (70% versus 65%) and OS (80%

versus 77%) benefits.

Pacitaxel 200mg/m2 IV over 3 hrs on day 1, repeat cycle every

21 days.

Docetaxel 75 mg/m2IV on day 1,reapeat cycle every 21 days.

Paclitaxel1 bevacicizumab - Paclitaxel:90 mg/m2IV on days

1,8,15.

Bevacizumab;(Monoclonal antibody) anti vegf –antibody 10

mg/m2 on days 1 and 15,repeat Cycle every 21 days.

72

CHEMOTHERAPY RESPONSE ASSESSMENT

Tumour response assessment usually occurs 8-12 weeks after the

starting of chemotherapy and comprises a summary of radiological and

clinical responses, symptomatic benefit (including any improvement in

performance status) balanced against toxicities of treatment.

Radiological response (determined by response evaluation criteria in

Solid Tumours (RECIST) criteria, is an improvement guide to the

clinician in deciding whether to continue or change therapies.

While objective tumour responses (i.e., tumour shrinkage by more

than 30%; Table @) set the standard user in clinical trials to judge the

efficacy of chemotherapy, stabilisation of disease by RECIST criteria

with a symptomatic benefit is an equally important endpoint. In patients

with non-measurable disease, (e.g., bone-only disease) treated with

chemotherapy, serial tumour markers together with symptomatic benefit

are important indications of response to treatment.

73

Miller-Payne histological criteria for grading response to solid

tumours to chemotherapy in breast cancer.

Grade Description

1 No change

2 A minor loss up to 30% loss

3 Between 30% and 90% reduction in tumour cells

4

A marked disappearance of tumour cells

more than 90% loss of tumour cells

5

No malignant cells identifiable in sections from the

site of the tumour; only vascular fibroelastoticstroma

remains often containing macrophages. However,

ductal carcinoma in situ (DCIS) may be present

RADIOTHERAPY

The worldwide trend to be less radical treatment in the

management of Carcinoma Breast has led to increasing role of

radiotherapy in this disease. The first major use of radiotherapy in breast

cancer was adjuvant to radical mastectomy. As the risk of local

recurrence after mastectomy was 10 to 15% it was hoped that

prophylactic radiotherapy would decrease this. Fletcher has also stressed

74

the judicious use of postoperative radiotherapy since the probability of

control of gross local or regional recurrence from breast cancer is less

than 60%. Post operative radiotherapy helps to decrease chances of local

recurrence and increase local control & hence increase survival.

The technique of breast irradiation has evolved from use of

conventional two dimensional planning with and without using wedges

to 3 D conformal radiotherapy and intensity modulated radiotherapy

(IMRT). Standard opposed tangential fields with appropriate use of

wedges to optimize dose homogeneity remain the most commonly

employed method for delivery of whole breast irradiation. These

approaches include multicatheter interstitial implants placed around the

excision cavity, single balloon catheter that can be afterloaded with a

central radiation source (MammoSite) which is placed into the excision

cavity, external beam conformal partial breast irradiation, and

intraoperative single-dose irradiation.

Even after mastectomy and systemic therapy occult disease may

remain in the chest wall and or regional lymph nodes. The residual

disease may serve not only as a source of potentially morbid loco-

75

regional recurrence but also an important reservoir from which distant

metastases may be seeded after the initial elimination of distant disease

by systemic therapies. Therefor postmastectomy radiation therapy

(PMRT) is an essential part of the treatment. Postop RT decreases risk of

loco regional recurrence by treating residual microscopic disease that has

spread beyond margins of surgical resection. The term local recurrence

means the evidence of disease appearing in scar site or skin belonging to

breast anatomical area or nodal drainage areas after adequate primary

management.

Loco-regional failure can occur in the following sites

1. Ipsilateral chest wall/ Mastectomy Scar

2. Axillary Lymph nodes/Soft tissues

3. Supra/Infraclavicular Lymph nodes

4. Internal mammary Lymph nodes

Types

1. Skin 2. Scar 3. Nodal 4.Combined.

Local skin recurrence may be nodular or inflammatory. Nodular

may be solitary or multiple occurring most frequently in skin or

76

subcutaneous tissues in and around mastectomy scar. Small nodules are

usually asymptomatic while larger ones can cause pain, itching or

ulceration. In advanced situation confluent nodules may encircle chest to

form cancer encuirasse.

The inflammatory type also called as erypeseloid is less common.

The lesion appears as diffuse reddening of skin associated with slight

induration and increase in local temperature. Patients with this type of

recurrence have poor prognosis and usually die of widespread metastatic

disease within a short span of time. The scar recurrence is usually in the

form of nodules or ulcers. Lymph node recurrence takes the form of

nodules growing and getting fixed and ulcerating producing

lymphedema of arm and painful limitation of arm movements.

Principles Of Concurrent chemoradiation:

Concurrent chemoradiation has produced important improvements

in treatment outcome. Randomized clinic trials show improved local

control and survival through the use of concurrent chemotherapy and

radiation therapy for patients with high-grade gliomas and locally

advanced cancers of the head and neck, lung, esophagus, stomatch,

rectum, and anus.

77

The first is mechanism is radiosensitization.. The underlying

concept is that the observed effect of using chemotherapy and radiation

concurrently is greater than simply adding the two together synergy

cannot be determined simply by normalizing the radiation cell-survival

curve for drug-induced cytotoxicity

A second proposed reason to combine radiation and chemotherapy

is to realize the benefit of improved local control radiation along with the

systematic effect of chemotherapy; a concept called spatial additivity.

Although concurrent chemotherapy has improved survival and

organ conservation, further advances are limited by the toxicity of

treatment. For example, in the curative treatment of locally advanced

head and neck cancer with chemoirradiation. It is now standard toplace a

gastrostomy tube prophymucositis that they are unable to maintain

adequate nutrition orally. The toxicity of treatment resukts from the

relative lack of specificity of both radiation and chemotherapy for cancer

cells as opposed to rapidly dividing normal cells.

78

MECHANISMS OF LOCAL RECURRNECE

1. Extra mechanism is unknown Proposed theories include

2. Seedling from peripheral extensions of tumour

3. Implantation from vessels that ooze blood or lymph containing

tumour emboil.

4. Retrograde movement of tumour cells to edge of the wound

5. Immunological factors.

Chest wall is the most common site of recurrent disease,

accountiong for two-thirds to three-quarters of all local-regional

recurrences.

RISK CATEGORIES FOR LOCOREGIONAL RELAPSES

AFTER MATECTOMY AND AXILLARY CLEARANCE

RISK

CATEGORY

LOW INTERMEDIATE HIGH

RISK <10% 10-20% >20%

TUMOUR

STAGE

T1-T2 T1-T2 T3-T4

79

NO OF

AXILLARY

NODES

0 1-3 >3

GRADE 1-2 3

VASCULAR

INVASION

- +

HISTOLOGY DUCTAL LOBULAR

RISK OF AXILLARY RUCURRENCE

1-3 +VE LN (10YR-LRF)

2-5 LN dissected 7%

6-10 LN 5%

>11LN 1.5%

>4 +VE Ln (10yr-lrf)

4-5ln DISSECTED 12%

6-10 8%

>11 LN 6%

80

Early breast cancer Trialists’ collaborative group and 2002

Cochrance review have shown that postoperative radiotherapy decreases

recurrence rates by two their. Post operative RT decreases recurrences

rates in stage 1 by 5%, stage 2 by 10% and stage 3 by 10 to 15%.

81

REVIEW OF LITERATURE

ROLE OF SURGERY

Prospective Trials

The MF 07-01 9(NCT00557986) is phase 3 RCT that compares

metastatic breast cancers patients at presentation who receive loco

regional treatment Vs no treatment and to assess the overall survival

benefit, which was activated in 2007. Short interim remits in ASCO

2010 shows no evidence for surgery. Similar NCT 00193778 study from

India familiar to show such benefit.

The current evidence is not enough to use surgery for primary

MBC. However there is subset of patients who may be offered loco-

regional treatment such as surgery to maximize survival.

82

ROLE OF RADIOTHERAPY

Review of literature

.A study from the Centre René Huguenin (Paris, France), loco

regional radiotherapy was significantly associated with increased

survival on multivariable analysis. In this study they were rarely used

surgery as a primary treatment in metastatic breast cancer. They used

locoregional radiotherapy as a main modality. The conclusion in that

trial was locoregionalradiotherapy ,may be an alternate modality for

surgery in metastatic breast cancer with leess morbidity 11

Another study from the Institute Gustave-Rousse (Paris, France),

239 women with stage IV breast cancer received loco regional treatment,

either with radiotherapy alone or surgery with or without radiotherapy.

In this study there was no significant difference in overall survival was

observed, again it showed that radiotherapy, without surgery, was an

adequate loco regional treatment metastatic breast cancer of women.

Retrospective Studies

A trial from Tata Memorial Hospital (Mumbai, India) was

initiated in 2005.] In this trial, chemotherapy is given before any

83

locoregional treatment. Preliminary results reported that 72% of patients

in the locoregional treatment arm are free of disease progression

compared with 61% in the observation arm. On multivariable analysis,

locoregional treatment is a significant factor for progression-free

survival.

84

THEORETICAL ADVANTAGES OF LOCOREGIONAL

TREATMENT OFTHE PRIMARY DISEASE BY SURGERY

1. The removal of the intact primary tumor has been

hypothesized to potentially reduce hematogeneous seeding by

micrometastatic populations since local disease may serve as a

hub of tumor stem cells

2. Another theoretical advantage of loco regional treatment in the

setting of stage IV disease can reduce levels of circulating tumor

cells that improved disease response and survival, and longer time

to progression are associated with a lower number of circulating

tumor

3. .Some biologists contend that tumor dissemination can

compromise the immune system. The primary tumor can produce

immunosuppressive factors that may help cancer cells avoid

eradication by the immune system. In this context, surgical

resection can reduce tumor load and lessen harmful immuno-

suppression.

85

o A Theoretical Disadvantage of local therapy is based on the

hypothesis that the primary local tumor can secrete substances that

inhibit new blood vessels that support tumor growth.

o Removal of the primary disease can induce an angiogenic surge

and promote the progression of metastases.

o Some believe that trauma induced by surgical intervention and

general anesthesia can generate cytokines that stimulate neoplastic

proliferation and compromise the integrity of the immune system.

Advantages of radiotherapy

Radiotherapy is a scientific surgery

1. Non invasive

2. No risk of anaesthesia

3. No risk of comorbidities

4. Can be given in patients with disseminated disease.

5. Skin is the best dressing and protection of the tumor which is not

disturbed .

6. Cost effective , no need of hospital admission

86

AIM OF THE STUDY

Aim of this retrospective study is to evaluate the role of loco

regional treatment such as local radiotherapy and surgery in the

management of patient with metastatic breast cancer.

METHODS AND MATERIALS

Study design: This study is a retrospective study to evaluate the

role of 11 loco regional treatment such as radiotherapy and surgery in

Metastatic Breast Cancer.

Inclusion and exclusion criteria

Inclusion criteria

In our retrospective study we reviewed female patients with metastatic

breast cancer registered at cancer Institute were analyzed from the year

2003 to 2008.

Inclusion criteria for this study were the following

Study setting

All medical records of female patients with metastatic breast

cancer registered at cancer Institute from the year 2003 TO 2008 and

87

who fulfil the inclusion and exclusion criteria of the study were reviewed

and included in this study

Duration of the study

patients from the year 2003 to 2008

SAMPLE SIZE:

195 patients (120 patients underwent loco regional treatment 75

no treatment)

TREATMENT PROTOCOL

All patients were treated with chemotherapy with or without

concurrent radiotherapy. After six months of initial treatment response

was assessed and decision regarding surgery was taken. Radiotherapy

was given concurrently with chemotherapy.

Whole Breast Irradiation

Treatment volume

The areas treated generally include the whole breast with or

without supraclavicular, axillary regions. The entire breast and chest

wall are included in the irradiated volume. The upper margin of the

88

portals should be placed at the head of the clavicle to include the entire

breast. The medial margin should be at or 1cm over the midline. The

lateral posterior margin should be placed 2cm beyond all palpable breast

tissue. Which is usually near the mid-axillary line. The inferior margin is

drawn 2 to 3 cm below the inframammary fold. In patients treated with

6-MV or lower energy photons with side tangential fields.

The entire ipsilateral breast should be encompassed. Conventional

field borders are used. BREAST is treated using two tangential fields,

medial and lateral tangents. Superior border is kept at second intercostal

space. Medical border is at midline or matched with internal mammary

89

field when used. Lateral border is kept at midaxillary line. Inferior

border is at 2 cms below opposite inframammary fold.

SUPRACLAVICULAR FIELD

Supraclavicular nodes are ususlly encompassed, with a single

anterior oblique photon field angled slightly away from the spinal cord.

The medial border is placed at the insertion of the clavicular head. The

lateral border is placed to include approximately one-third of the

humeral head. The inferior border is the inferior border of the clavicle or

the superior border of the chest wall field. The superior border is set at

the thyrocricoid groove. A humeral head block is added to block the

humeral head and acromioclavicular join 54

To avoid the problem of hot spot whoile matching supraclavicular

and chest wall fields following methods are used. Angling the foot of the

treatment couch away from the radiation source to direct the tangential

fields inferiorly so that superior edge of these beams line up perfectly

with inferior border of supraclavicular field. We canalso used the three

field single isocentre technique or Hanging block technique. Half beam

block can also be used.

90

INTERNAL MAMMARY FIELD

The internal mammary chain lies beside the sternum, generally in

the first through the third intercostal space, althoiugh the depth may

vary. Various methods of encompassing the ionternbal mammary chain

have been described, including extended tangent fields, partially wide

tangent fields and matching electron and photon fields. But prophylactic

internal mammary nodal irradiation is not recommended even in medial

quadrant tumors.40

POSTERIOR AXILLARY BOOST

The dose provided to the axillary nodes through the

supraclavicular/axillary field can sometimes creat suboptimal dose

distributions to deeper lying level 3 axillary nodes. If coverage is

suboptimal, the dose can be supplemented with a posterior axillary field.

The field is set up opposed to the supraclavicular/axillary field. The

medial border of this field is drawn to allow 1.5 to 2 cm of lung. If the

inferior border is at the same level as the inferior border of the

supraclavicular field, the lateral border just blocks falloff across the

posterior axillary fold, the superior border splits the clavicle, and the

superolateral border shields or splits the humeral head. 54

91

DOSE

Most commonly employed dose schedule is 40-45Gy in 22- 25

fractions at conventional 180cGy daily for 5 weeks

92

93

DOSE VOLUME HISTOGRAM

FOLLOW UP

Subsequently patients were followed up monthly for the first year

and once in threemonths for a period of five years from date of

completion of radiotherapy after 5 years yearly follow-up was done

ASSESSMENT TOOLS

Medical records were reviewed for the following factors.

1. age at diagnosis

2. laterality

94

3. histology of the tumor

4. clinical and pathologic size of the primary tumor

5. lymph node status

6. hormone receptor status

7. her 2 over expression

8. location and number of metastases mode

9. date of surgical treatmen

10. t, margin status,

11. use of radiotherapy

12. systemic therapy

13. The time of death

14. the time of last review among alive patients

15. Patients with metastatic Breast cancer excluding brain metastasis

at presentation were included.

95

Patients baseline charecteristics

FACTOR NO OF CASES SURVIVAL PERCENTAGE

1 yr 3 yr 5 yr 10 yr

All cases 188 78 43 35 30

Pre Menopause 65 77 43 35 26

Post menopause 112 80 41 33 31

ER negative 55 75 40 36 34

ER positive 84 82 54 42 37

PR negative 66 76 41 33 32

PR positive 66 82 56 45 39

Her2 negative 31 94 68 61 58

Her2 positive 14 79 36 36 36

Metastasis 1 31 90 65 55 50

Metastasis 2 68 82 53 43 37

Metastasis 3 18 61 22 17 10

Metastasis 4 20 85 55 50 45

Metastasis 6 38 68 21 13 7

Metastasis 7 3 67 0 0 0

Metastasis 8 7 71 14 14 14

96

MENOPAUSAL STATUS

0

20

40

60

80

100

120

premopausal postmenopausal

NO OF PATIENTS

NO OF PATIENTS

Most of the patients in this study were premenopausal.

ESTROGEN RECEPTOR STATUS

0

10

20

30

40

50

60

70

80

90

Estrogen +ve Estrogen-ve

HR status

97

Estrogen receptor status No of patients

ER+ve 84

ER-ve 56

Status not known 55

PROGESTRONE RECEPTOR STATUS

98

PR STATUS NO OF PATIENTS

PR+VE 66

PR-VE 66

Results

Tumour stage of the patients

Out of 195 patients 118 had T3 tumor size and 37 pts had T4

disease ,remaining 36 patients comes under T1,T2,T0

Tumor size No of pts

T4 37

T3 118

T1,T2,T0 36

99

T 4 T 3 T 1 , T 2 , T 0

37

118

36

SERIES 1

Most common tumour stage was T3

NODAL STAGE OF THE PATIENTS

24% of the patients had N3 disease and 31 had N2 stage , 36% of

them had N1 and 9%

Had N0 disease

NODAL STAGE PERCENTAGE OF PATIENTS

N3 24

N2 31

N1 36

N0 9

100

24%

31%

36%

9%

NODAL STAGE

N3 N2 N1 N0

Most common nodal stage was N1

Out of 195 pts 86 pts are hormone receptor positive and in 109 pts

the details of Receptor status not known.

101

Receptor status No

HR positive 86

HR not known 109

Her2neu status of the patients

Graph:Precentage of patients with left and right sided tumours

102

54%

46%

0% 0%

Most common sides

In this study right sided tumours were found to be more common

than left side tumours.

Incidence of bone metastasis

Out of 195 patients 33 patients (32%) had single bone metastasis

and 70 patients (68%) had multiple bone metastasis

NO OF BONE METASTASIS NO OF PATIENTS

SINGLE METS 33

MULTIPLE METS 70

103

Graph : Percentage of pts with single and multiple bone metastasis

LIVER AND LUNG METASTASIS

out of 195 total patients 18 patients (9%) had liver metastasis and

21 patients (11%) had lung metastasis ,two patients (1%) had both liver

and lung metastasis.

Site of metastasis No of patients

Liver 18

Lung 21

Both liver and lung 2

104

Patients with multiple metastasis

40 patients (21%) had multple visceral and nonvisceral metastasis

excluding brain which is not included in the study.

105

Total no of pts 195

Multiple mets 40

code for various treatment options

1. code for various treatment options

2. chemoirradiation (RT+CT)

3. chemotherapy +surgery (CT+SX)

4. Chemoirradiation + surgery(CT+RT+SX)

5. Chemotherapy only (CTonly)

106

6. Radiotherapy only (RT only)

7. chemotherapy +hormone therapy (CT+HT only)

8. radiotherapy +hormone therapy (RT+HTonly)

9. chemotherapy+radiotherapy+hormone therapy (CT+RT+HT)

Various treatment OPTIONS

Out of 195 patients with Metastatic Breast Cancer,

74 patients received chemoirradiation.

37 patients received chemoirradiation and then underwent surgery.

44 patients received chemotherapy alone.

3 patients received radiotherapy alone.

2 patients received chemotherapy and surgery.

Total no of patients 195

chemoirradiation 74

CT +SX 37

CT 44

RT 3

SX 2

107

108

CHEMOIRRADIATION

Out of 195 patients 74 patients received chemoirradiation .

RESULTS

In patients receiving CT+RT survival at the end of 1 yr was

(89%) 3 yr (58%) 5 yr (46%) 10 yr,(42%).

109

CHEMORADIATION AND SURGERY

Out of 195 patients 37 patients received chemoirradiation

and then underwent surgery.

37

158

CT +SX other patients 158

RESULTS;

In patients receiving CT+RT + surgery at the end of 1 yr was

(97%) 3 yr (80%) 5yr(70%) 10 yr,(71%).

110

CHEMOTHERAPY

Out of 195 patients with Metastatic Breast Cancer

44 patients received chemotherapy alone.

44

151

received chemotherapy 44 other patients 151

RESULTS

In patients receiving CT only at the end of 1 yr was (60%) 3 yr

(5%) 5yr(2%) 10 yr,(0%).

111

RADIOTHERAPY

Out of 195 patients with Metastatic Breast Cancer 3

patients received radiotherapy alone.

RESULTS:

In patients receiving RT only at the end of 1 yr was (67%) 3 yr

(33%) 5yr(33%) 10 yr,(33%).

112

CHEMOTHERAPY AND SURGERY

OUT OF 195 PATIENTS RECEIVED chemotherapy and surgery

2

193

00

.

patients received chemotherapy and durgery other patients

Hormonal therapy

8 patients received hormonal therapy alone.

12 patients got chemotherapy and hormonal therapy

5 patients received radiotherapy and hormonal therapy.

6 patient srecivedhemoirradiation and hormonal therapy

113

NO OF PATIENTS 195

HT 8

CT+HT 12

RT+HT 5

CT+RT+HT 6

HORMONAL THERAPY

Out of 195 patients with Metastatic Breast Cancer

8 patients received hormonal therapy alone.

patients received hormonal therapy other patients

In patients receiving HT only at the end of 1 yr was (50%)

3 yr (13%) 5yr (13%) 10 yr,(13%).

114

Chemotherapy and hormonal therapy

Out of 195 patients with Metastatic Breast Cancer12 patients got

chemotherapy and

hormonal therapy

In patients receiving CT+HT at the end of 1 yr was (58%) 3yr (8%)

5yr(0%) 10 yr,(0%).

115

Radiotherapy and hormonal therapy

Out of 195 patients with Metastatic Breast Cancer

5 patients received radiotherapy and hormonal therapy

.

In patients receiving RT + HT at the end of 1 yrsurvival

was (50%) 3yr(0%) 5yr(0%) 10 yr,(0%).

Chemoirradiation and hormonal therapy. Out of 195 patients with

Metastatic Breast Cancer 6 patientsrecived Chemoirradiation and

hormonal therapy.

116

6

189

00

patients recived chemoirradiation and hormonal therapy. other patients

In patients receiving CT+RT + HT survival at the end of 1 yr was (67%)

3yr(50%) 5yr(0%) 10 yr,(0%).

VARIUOS TREATMENT MODALITIES

39%

23%

19%

2%1%

4%

6%3% 3%

CT+RT CT CT+RT+SX RT CT+SX HT CT+HT RT=HT CT+RT+HT

117

FACTOR NO OF CASES SURVIVAL PERCENTAGE

1 yr 3 yr 5 yr 10 yr

Treatment modality

0 4 50 25 25 0

2 72 89 58 46 42

3 1 100 100 100 100

5 35 97 80 77 71

6 43 60 5 2 0

7 3 67 33 33 33

8 8 50 13 13 13

9 12 58 8 0 0

10 4 50 0 0 0

11 6 67 50 0 0

V Out of 195 patients 74 patients received chemoirradiation and then

underwent surgery.

118

FACTOR NO OF CASES SURVIVAL PERCENTAGE

1 yr 3 yr 5 yr 10 yr

All cases 188 78 43 35 30

Pre Menopause 65 77 43 35 26

Post menopause 112 80 41 33 31

ER negative 55 75 40 36 34

ER positive 84 82 54 42 37

PR negative 66 76 41 33 32

PR positive 66 82 56 45 39

Her2 negative 31 94 68 61 58

Her2 positive 14 79 36 36 36

Metastasis 1 31 90 65 55 50

Metastasis 2 68 82 53 43 37

Metastasis 3 18 61 22 17 10

Metastasis 4 20 85 55 50 45

Metastasis 6 38 68 21 13 7

Metastasis 7 3 67 0 0 0

Metastasis 8 7 71 14 14 14

FACTOR NO OF CASES SURVIVAL PERCENTAGE

1 yr 3 yr 5 yr 10 yr

Treatment modality

0 4 50 25 25 0

2 72 89 58 46 42

3 1 100 100 100 100

5 35 97 80 77 71

6 43 60 5 2 0

7 3 67 33 33 33

8 8 50 13 13 13

9 12 58 8 0 0

10 4 50 0 0 0

11 6 67 50 0 0

119

Discussion

The purpose of the study was to evaluate the role of locoregional

treatment in metastatic breast cancer since this was a retrospective study

between the year of 2003 – 2008 all medical records of female metastatic

breast cancer patients excluding brain metastasis were revised and

analysed with a following factors such as menopausal status, hormone

receptor status, HER2 neu status, no of metastasis (including visceral

and non-visceral)

65 patients in this study were premenopausal and 112 patients

were belonged to postmenopausal group 55 patients were ER negative

and 84 patients were ER positive and out of 195 patients 14 patients

were HER2 positive and 31 patients were HER2 negative and in the

remaining cases status not known.

31 patients had single bone metastasis and 68 pts had multiple

bone metastasis 18 patients had liver metastasis and 21 patients had lung

metastasis 2 patients had metastasis liver and lung 3 patients with

supraclavicular metastasis 7 patients had axillary metastasis.

120

All patients underwent various treatment modalities according to

tumour board policy. 74 patients underwent chemo radiation 2 patients

had chemotherapy followed by surgery 37 patients got concurrent chemo

radiation followed by surgery. 44 patients received chemotherapy

alone.3 patients had only radiotherapy 12 patients received

chemotherapy and harmonic therapy 8 patients had harmonic therapy

only in 5 patients radiotherapy and harmonic therapy was given 6

patients had chemo radiation followed by hormonal therapy.

Patients survival was analysed at the end of 1 yr, 3 yr, 5 yr, and 10

years. In patients receiving CT+RT survival at the end of 1 yr was (89%)

3 yr (58%) 5 yr (46%) 10 yr,(42%). In patients receiving CT+RT +

surgery at the end of 1 yr was (97%) 3 yr (80%) 5yr(70%) 10 yr,(71%).

In patients receiving CT only at the end of 1 yr was (60%) 3 yr (5%)

5yr(2%) 10 yr,(0%). In patients receiving RT only at the end of 1 yr was

(67%) 3 yr (33%) 5yr(33%) 10 yr,(33%). In patients receiving HT only

at the end of 1 yr was (50%) 3 yr (13%) 5yr (13%) 10 yr,(13%).

In patients receiving CT+HT at the end of 1 yr was (58%) 3yr

(8%) 5yr(0%) 10 yr,(0%). In patients receiving RT + HT at the end of 1

121

yr was (50%) 3yr(0%) 5yr(0%) 10 yr,(0%). In patients receiving CT+RT

+ HTat the end of 1 yr was (67%) 3yr(50%) 5yr(0%) 10 yr,(0%).

Conclusion

The data reported in this retrospective study confirmed that

chemo-radiation improved overall survival and symptomatic local

control were demonstrated in locoregionally treated patients with

metastatic breast cancer. The optimal local management of patients with

metastatic breast cancer remains unknown. An ongoing phase III trial,

E2108, has been designed to assess the effect of locoregional

management in metastatic patients responding to first-line systemic

therapy.Loco regional radiation can be an integral part in metastatic

breast cancer treatment to improve the quality of life. If the patient did

not have any metastasis at the end of one year mastectomy can be added

to still more improve the local control according to this study as there is

a significant overall survival and better local control with concurrent

chemo radiation hence RT has a integral part in the management of

metastatic breast cancer.

122

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